The eukaryote genome constantly faces the threat of damage from exogenous and endogenous mutagens. Mammalian cells, therefore, have evolved an intricate network of defenses to maintain genomic stability. p53 is at the crossroads of these defense pathways. We investigate rare genomic instability and/or premature aging diseases, e.g., Bloom, Werner, Rothmund-Thomson, and Li-Fraumeni Syndromes, to gain insight into p53 function in the general population. For example, p53-mediated apoptosis is also modulated by the human RecQ family of DNA helicases. p53 also facillitates DNA repair pathways. We have also discovered transcriptional cofactors of p53, i.e., ING2-5, that enhance p53 effector functions in cell cycle checkpoints, apoptosis, and senescence. ING4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha1. Novel splice variants of ING4 have also been discovered. We are continuing to study p53-mediated replicative senescence modulated by either ING family proteins or by POT1 and p53 isoforms that govern telomere attrition.